We have undertaken a study to identify the critical genetic events in the pathogenesis of human cancer. We have currently our efforts on studying the mechanism and implication of inactivation of the retinoblastoma (Rb) gene in human cancer. Our recent findings are as follows: 1) essentially all small cell lung cancer tumors have absent or aberrant-- Rb protein products; 2) we have identified and characterized a series Rb mutants (defective in phosphorylation and oncoprotein binding); 3) we are investigating the possibility of these Rb to function as transforming genes (dominant negative effect); 4) we have successfully transfected a wild-type or Rb gene in a SCLC cell line to study its biological effect; and 5) we are using our Rb open reading frame reagents to identify putative cellular proteins that normally interact with the Rb protein and presumably modulate its growth inhibitory effect. In addition, we continue to maintain a research effort studying of L-myc gene activation and plan to purify and characterize several specific L-myc DNA binding protein which we have previously characterized.